Process for the synthesis of l-fucosyl di- or oligo-saccharides and novel 2,3,4 tribenzyl-fucosyl derivatives intermediates thereof

Abstract

The present invention relates to a process for the synthesis of L-fucosyl di- or oligosaccharides and their novel 2,3,4-tri-O-benzyl-fucosyl synthetic intermediates derivatives of easy crystallization. In particular the present invention relates to a process applicable to industrial scale for the synthesis of 2′O-fucosyl lactose.

1 . A process for synthesis of fucosyl derivatives of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R is a monosaccharide, a disaccharide or an oligosaccharide with free hydroxy groups; 
         the process comprising using an intermediate of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein P is independently among each other are benzyl groups of formula 
       
       
         
           
           
               
               
           
         
         wherein R1 is chosen among chlorine, bromine, alkoxy and nitro; R2 is chosen among hydrogen, chlorine, bromine, alkoxy and nitro; 
         R″ is, correspondingly to R, a monosaccharide, disaccharide or an oligosaccharide, whose hydroxy groups are free or partially protected by benzyl groups; 
         wherein said hydroxy groups protected by benzyl groups are groups —OCH 2 Ph or —OP; and wherein hydroxy groups partially protected by benzyl groups means that given a number n of hydroxyls present on R″ at the most n/2 when n is an even number or (n−1)/2 when n is an odd number they are protected by said benzyl groups. 
       
     
     
         2 . The process according to  claim 1  comprising a step c) of removing benzyl groups from intermediate (IV) to obtain a compound of formula (I). 
     
     
         3 . The process according to  claim 2  wherein step c) is preceded by the following steps:
 a) coupling of a 2,3,4-tri-O-benzyl-fucopyranosyl derivative donor of formula (II) 
 
       
         
           
           
               
               
           
         
         wherein P is as above described; X is an anomeric carbon activator; 
         with a monosaccaride, disaccaride or oligosaccaride glycosyl acceptor of formula R′OH wherein R′ is, correspondingly to R, a monosaccharide, disaccharide or oligosaccharide suitably protected whose hydroxy groups for a maximum of 2 are free, optionally are partially protected by benzyl groups, the remaining hydroxy groups are protected with state of the art groups such to be removed in conditions such as to preserve benzyl groups and particularly to preserve groups —OP present on the fucosyl moiety; 
         to obtain intermediate of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein P and R′ are as above described; 
         b) removal of removing protecting groups of the saccharide moiety R′ in conditions such as to preserve groups —OP present on the fucosyl moiety and optionally preserve benzyl groups present on R′; 
         to obtain intermediates of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R″ and P are as above. 
       
     
     
         4 . A compound 2,3,4-tri-O-benzyl-L-fucosyl derivative of formula (II) or (IV) 
       
         
           
           
               
               
           
         
         wherein 
         P independently among each other are benzyl groups of formula 
       
       
         
           
           
               
               
           
         
         wherein R1 is chosen among chlorine, bromine, alkoxy and nitro; R2 is chosen among hydrogen, chlorine, bromine, alkoxy and nitro; 
         X is imidate; 
         R″ is a monosaccharide, disaccharide or oligosaccharide, whose hydroxy groups are free or partially protected by benzyl groups; 
         excluding that for a compound of formula (II) R2 is hydrogen when X is trichloroacetimidate and R1 is p-chloro. 
       
     
     
         5 . The compound of formula (IV) according to  claim 4  wherein R″ is chosen among lactose, fucose, (2-acetylamino)-lactose, (2-amino)-lactose, (2-azido)-lactose, Lacto-N-biose, galactose, glucose, (2-acetylamino)-glucose, (2-amino)-glucose and (2-azido)-glucose whose hydroxy groups are free or partially protected by benzyl groups. 
     
     
         6 . The compound according to  claim 5  wherein R″ is chosen among 2′-lactose, 3-lactose, 3-(2-acetylamino)-lactose, 3-(2-amino)-lactose, 3-(2-azido)-lactose, 4-Lacto-N-biose, 2-galactose, 3-glucose, 3-(2-acetylamino)-glucose, 3-(2-amino)-glucose, 3-(2-azido)-glucose 4-(2-acetylamino)-glucose, 4-(2-amino)-glucose and 4-(2-azido)-glucose whose hydroxy groups are free or partially protected by benzyl groups. 
     
     
         7 . A compound according to  claim 6  wherein R″ is 2′-lactose that is compounds of-formula (IVa) 
       
         
           
           
               
               
           
         
         wherein P is as above described; R4 is hydrogen, benzyl or P. 
       
     
     
         8 . A method for synthesizing a compound of formula (IV) according to  claim 4 , the method comprising
 using a fucosyl donor a compound of formula (II) wherein X is an anomeric carbon activator chosen among an imidate or an halogen; P independently among each other are benzyl groups of formula   
       
         
           
           
               
               
           
         
         wherein R1 is chosen among chlorine, bromine, alkoxy and nitro; R2 is chosen among hydrogen, chlorine, bromine, alkoxy and nitro. 
       
     
     
         9 . The method according to  claim 8  wherein X is trichloroacetimidate or α-bromine. 
     
     
         10 . A method for synthesis of a compound of formula (I), the method comprising using a compound of formula (II) to as a fucosyl-donor for synthesising a compound of formula IV; and
 using the compound of formula (IV) as a fucosyl donor for synthesizing the compound of formula (I) with the process according to  claims 1 .